CN103380127A - Method for producing N-sulfonyl-substituted oxindoles - Google Patents

Method for producing N-sulfonyl-substituted oxindoles Download PDF

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CN103380127A
CN103380127A CN2011800681816A CN201180068181A CN103380127A CN 103380127 A CN103380127 A CN 103380127A CN 2011800681816 A CN2011800681816 A CN 2011800681816A CN 201180068181 A CN201180068181 A CN 201180068181A CN 103380127 A CN103380127 A CN 103380127A
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CN103380127B (en
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G·凯里格
M·J·福特
K·西格尔
S·施奈特尔
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Abstract

The invention relates to a method for the selective N-sulfonylation of oxindoles, in particular a method for the N-sulfonylation of 3-triazinyl oxindoles, to N-sulfonyl-substituted 3-triazinyl oxindoles, and to the use of N-sulfonyl-substituted oxindoles and N-sulfonyl-substituted 3-triazinyl oxindoles as intermediate products for the synthesis of fine chemicals and active substances in the pharmaceutical and agricultural fields, and to the use of said compounds as active substances in the agricultural field.

Description

Process for preparing N-sulfonyl substituted oxindoles
The present application relates to a process for the selective N-sulfonylation of oxindoles, in particular of 3-triazinyl oxindoles, and to their use as intermediates for the synthesis of fine chemicals and active ingredients in the agricultural field.
Furthermore, the application relates to N-sulfonyl-substituted 3-triazinyl oxindoles and their use as intermediates for the synthesis of fine chemicals in the agricultural field.
The processes known from the prior art for the N-sulfonylation of oxindoles are generally not directed to carrying out this reaction on an industrial scale. The use of activators for the processes known to date, in particular bases for deprotonation, is therefore unsuitable for carrying out the reaction on an industrial scale.
Furthermore, the prior art does not disclose a general rule for the preparation of N-sulfonyl-substituted oxindoles as selectively as possible. It is known that the sulfonylation reaction of oxindoles can proceed nonselectively depending on the reaction conditions, where, instead of the desired N-sulfonylated oxindole, O-sulfonylated products or disulfonylated, i.e.sulfonylated on oxygen and nitrogen, products can be formed.
Examples demonstrating the relatively low selectivity of sulfonylation of oxindoles are available, for example, from Synthetic Commun (1992)22, 2987 or org.biomol.chem. (2009)7, 3413. In this connection, it is believed that the possibility of the formation of O-sulfonylation products is increased, in particular for oxindoles, in which at least one of the substituents in position 3 is hydrogen.
Deprotonation
Deprotonation of oxindoles in position 1 precedes their sulfonylation, which is probably an important prerequisite for the selectivity of sulfonylation. Furthermore, the substitution of the oxindole skeleton, in particular in the presence of a base as activator, can likewise be decisive for the sulfonylation.
It is known that hydrogens on heteroatoms in aliphatic, aromatic and heteroaromatic compounds may be replaced with functional substituents (e.g., sulfonyl groups). It is also known to react N-unsubstituted or N-monosubstituted amides with sulfonylating agents (e.g., sulfonyl chlorides) in the presence of bases to obtain N-sulfonamides.
However, the amidosulfonylation reaction can also be carried out with weak bases, such as pyridine or triethylamine, which are known (Blakemore, P.R.: N-sulfonation of Amides, science of Synthesis, 21(2005), page 879), and this reaction is in most cases more successful if the deprotonation of the substrate is carried out with strong bases, such as sodium hydride, butyllithium or lithium hexamethyldisilazane, in which case the deprotonation is preceded by the addition of a sulfonylating agent to the nucleophilic amide anion resulting from the deprotonation.
N-sulfonyl substituted oxindoles
Compounds which may be prepared by the methods specified in the preceding paragraph are, for example, optionally substituted oxindoles (1, 3-dihydro-2H-indol-2-ones) in which, in the 1-position, the hydrogen is replaced by a sulfonyl substituent. These compounds are known as N-sulfonyl substituted oxindoles.
Phenyl-substituted oxindoles
A subgroup of N-sulfonyl substituted oxindoles are those with a phenyl substituent in position 3. Examples of the synthesis of such compounds (wherein, at the 1-position, the hydrogen is replaced by a sulfonyl substituent) may be selected from, for example, FR2714378, US1997/5594023, US2004/180878, US2005/70718, WO2006/110917, WO2006/072458, WO2006/100080, WO2006/100081, WO2006/100082, WO2008/107399, WO2008/025735, US2008/318923, US2009/318406 and bioorg.med.chem.lett. (1998), 8, 175; commun. (2009)26, 3955.
The common feature of the reactions disclosed in the above prior art is that a strong base (e.g. sodium hydride or potassium tert-butoxide) is used in the sulfonylation reaction. However, these strong bases are sensitive to water and therefore cannot be restored to an undecomposed state after aqueous post-treatment. Furthermore, these strong bases disadvantageously lead to the formation of equimolar amounts of elemental hydrogen and are therefore also expensive. Therefore, the industrial use of these bases is disadvantageous.
There is hardly any example in the prior art of the use of the weak base triethylamine for the sulfonylation of oxindoles substituted in the 3-position by phenyl groups and also by imidazol-1-yl groups (European Journal of medicinal chemistry (1981), 16, 373). However, the chemical yield of the sulfonylation reaction of the above publication is only 12%, and is therefore unsuitable for use on an industrial scale (example 1, variant F).
Heteroaryl substituted oxindoles
Oxindoles bearing one heteroaryl substituent in position 3 form another subgroup of N-sulfonyl substituted oxindoles. Examples of reactions to obtain N-sulfonyl substituted oxindoles with a 6-ring heteroaryl substituent in position 3, wherein the hydrogen in position 1 is replaced by a sulfonyl substituent, are 3- (3-pyridyl) substituted oxindoles (US2005/70718, WO2009/083559, WO2008/80970), or 3- (3, 5-pyrimidinyl) substituted oxindoles (US 2005/70718). However, the reactions disclosed in the above prior art have in common the feature that strong bases (such as sodium hydride or potassium tert-butoxide) are used in the sulfonylation reaction, the application of which on an industrial scale has the disadvantages described above.
N-sulfonylation of phenyl-substituted oxindoles with sodium carbonate
Scheme 1 summarizes the known processes for the N-sulfonylation of oxindoles which carry a phenyl ring as a substituent in the 3-position (J.chem.Soc. (1957), 4789-4798). This process is worth mentioning that it is not carried out using a strong base (for example sodium hydride or potassium tert-butoxide) as in the reactions disclosed in the above prior art, but in water/acetone with sodium carbonate as base. For the reaction of the 3-phenyloxindole A with 4-methylbenzenesulfonyl chloride, the product B3-phenyl-1-toluene-p-sulfonyloxindole was obtained and the indicated yield was 41%.
Scheme 1-reaction of 3-phenyloxindole with 4-methylbenzenesulfonyl chloride as sulfonylating agent:
Figure BDA0000369980320000031
for comparison purposes, the reaction was carried out anew under the conditions described in J.chem.Soc. (1957), 4789-4798, page 4796 for the reaction of 3-phenyloxindole using 4-methylbenzenesulfonyl chloride as sulfonylating agent and sodium carbonate in water/acetone as base. After isolation of the product, it was confirmed by NMR analysis that in this reaction, the major component formed was not the putative N-sulfonylated product B but O-sulfonylated product C (example 11). Therefore, the methods known from j.chem.soc. (1957), 4789 are not suitable for the preparation of N-sulfonyl substituted 3- (phenyl) oxindoles.
N-sulfonyl substituted 3-triazinyl oxindoles
N-sulfonyl substituted 3-triazinyl oxindoles which form another subgroup of N-sulfonyl substituted oxindoles substituted at the 3-position with heteroaryl have not been described in the prior art. The same is true for the preparation of N-sulfonyl substituted 3-triazinyl oxindoles.
A group of N-sulfonyl-substituted 3-triazinyl oxindoles which is of particular economic importance are those C which are completely or partially fluorine-substituted with N-sulfonyl groups1-C6Alkyl, especially difluoromethyl and trifluoromethyl, or (C)3-C7) -compounds of substituents of cycloalkyl groups. These compounds are suitable as active ingredients in pharmacy or agriculture or as intermediates for the preparation of fine chemicals and active ingredients in the pharmaceutical or agricultural field.
Also for comparison purposes, the conditions described in J.chem.Soc. (1957), 4789-4798, page 4796 also apply to the reaction of 3- (triazinyl) oxindole with 4-methylbenzenesulfonyl chloride. However, it was likewise not the N-sulfonylated product formed, but an O-sulfonylated product, as detected by UV absorption and NMR analysis (example 13). The described process is therefore likewise unsuitable for preparing N-sulfonyl-substituted 3-triazinyloxyindoles.
N-sulfonylation of phenyl-substituted oxindoles with sodium hydride
US2009/0318406 discloses a method of sulfonylation at the 1-position of an oxindole bearing a substituted benzene ring or a substituted piperazine ring as substituent at the 3-position. The process is carried out at 0 ℃ in tetrahydrofuran as solvent using sodium hydride as base.
Also for comparison purposes, the conditions described in US2009/0318406, page 19, paragraph 243 also apply to the reaction of 3-triazinyloxyindole with difluoromethanesulfonyl chloride. However, after a reaction time of 12 hours it was determined that little conversion to the desired product had occurred (example 1, variant D). The process described in US2009/0318406, at least when using difluoromethanesulfonyl chloride as sulfonylating agent, is therefore not suitable for the preparation of N-sulfonyl-substituted 3-triazinyl oxindoles on an industrial scale.
N-sulfonylation of phenyl-substituted oxindoles with potassium tert-butoxide
US2010/69384 discloses a method of sulfonylation of oxindoles in the 1-position with a substituted benzene ring and a methyl group as substituents in the 3-position. The process is carried out at-30 ℃ using potassium tert-butoxide as a base in tetrahydrofuran as a solvent.
Also for comparison purposes, the conditions described in US2010/69384, page 15, example 7A also apply to the reaction of 3- (triazinyl) oxindole with difluoromethanesulfonyl chloride. However, after a reaction time of 12 hours it was determined that little conversion to the desired product had occurred (example 1, variant E). The process described in US2010/69384, at least when difluoromethanesulfonyl chloride is used as sulfonylating agent, is therefore not suitable for the preparation of N-sulfonyl-substituted 3-triazinyl oxindoles.
A method of sulfonylation of oxindoles substituted with a phenyl group and an imidazol-1-yl group at the 3-position disclosed in European Journal of Medicinal Chemistry (1981), 16, 373 has been discussed. The process is worth mentioning that dichloromethane is used as solvent and triethylamine is used as base.
Also for comparison purposes, the conditions described in Journal of Medicinal Chemistry (1981), 16, 373 apply to the reaction of 3- (triazinyl) oxindole with difluoromethanesulfonyl chloride. However, it was determined that little conversion to the desired product occurred after a reaction time of 3 hours and 15 hours of standing (example 1, variant F). The described process, at least when using difluoromethanesulfonyl chloride as sulfonylating agent, is therefore not suitable for the preparation of N-sulfonyl-substituted 3-triazinyloxyindoles.
On this background, it is an object of the present invention to provide the most selective possible process for obtaining N-sulfonyl-substituted oxindoles with a six-membered heteroaryl group in position 3 on an industrial scale.
Surprisingly, it has now been found that N-sulfonyl-substituted 3-triazinyloxyindoles (3-1) can be prepared in good to very good selectivity by: the preparation is carried out in the presence of imidazole substituted in position 1 or a mixture of imidazole substituted in position 1 with a tertiary amine base or a mixture of imidazole substituted in position 1 with a substituted pyridine base, replacing the hydrogen atom in position 1 of the optionally substituted 3-triazinyloxyindole (1) with a sulfonyl compound (2) carrying a suitable leaving group X (scheme 2).
Scheme 2-Synthesis of N-sulfonyl substituted 3-triazinyloxyindole (3-1)
Figure BDA0000369980320000051
(1) 3- (triazinyl) oxindoles
(2) (ii) sulfonylating agent
B ═ imidazole bases substituted in the 1 position or base mixtures containing imidazole bases substituted in the 1 position
The fact that imidazoles, as bases, have the advantage-in their action as bases-that they are suitable for use on an industrial scale, since they are not decomposable, in particular in the presence of water, and they do not generate equimolar amounts of hydrogen.
The object is thus achieved by a process for preparing N-sulfonyl-substituted oxindoles of the formula (3) having a 6-ring heteroaryl substituent (Q) in position 3,
Figure BDA0000369980320000052
wherein
R1aTo R1dIndependently of one another, are selected from
Hydrogen, fluorine, chlorine, bromine, iodine, and is selected from
(C1-C6) -an alkyl group, wherein the alkyl group is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluorine, chlorine, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C3-C7) -cycloalkyl, wherein cycloalkyl is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)3-C7) -cycloalkyl or (C)1-C4) -a substituent of an alkoxy group,
(C1-C6) -alkoxy, wherein alkoxy is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C3-C7) -cycloalkoxy, wherein cycloalkoxy is unsubstituted or substituted with one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
(C1-C6) Alkylthio, wherein alkylthio is branched or unbranched and is unsubstituted or substituted by one or more substituents selected from the group consisting of fluorine, chlorine, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
(C3-C7) Cycloalkylthio radicals, in which the cycloalkylthio radical is notSubstituted or substituted by one or more groups selected from fluorine, chlorine, (C)1-C4) -alkyl or (C)1-C4) -substituent substitution of alkoxy, and
phenyl or 1-naphthyl or 2-naphthyl or a five-or six-membered heteroaromatic ring having 1 to 2 heteroatoms, wherein the heteroatoms are independently of one another selected from O or N and wherein aryl or heteroaryl is unsubstituted or is substituted by one or more groups selected from fluorine, chlorine, bromine, iodine, (C)1-C4) Alkyl radicals, (C)1-C4) -alkoxy or (C)3-C7) -cycloalkyl or (C)1-C4) -substituent substitution of alkylthio, and
R2is composed of
(C1-C6) -alkyl, wherein alkyl is unsubstituted or fully or partially substituted by fluorine, or
(C3-C7) Cycloalkyl, wherein cycloalkyl is unsubstituted or fully or partially substituted by fluorine,
R3is composed of
Hydrogen or
(C1-C6) -an alkyl group, wherein the alkyl group is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluorine, chlorine, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C1-C6) Alkylthio, wherein alkylthio is unsubstituted or substituted by one or more substituents selected from the group consisting of fluorine, chlorine, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
and
q is
A six-membered heteroaromatic ring having 1 to 3 nitrogen atoms, wherein the heteroaromatic ring is unsubstituted or is substituted by one or more substituents selected from (C)1-C4) -alkyl or (C)1-C4) -alkoxy or (C)3-C7) -cycloalkyl or (C)3-C7) A cycloalkoxy group or (C)1-C4) -a substituent of an alkylthio group,
by oxindole compounds of the formula (1)
Figure BDA0000369980320000071
Wherein
R1aTo R1dAnd R3And Q has the definition as defined in formula (3),
preparation by reaction with sulfonyl compound (2) in solvent
Figure BDA0000369980320000073
Wherein
R2Has the meaning as defined in formula (3), and
x, as leaving group, is
Fluorine, chlorine, bromine, 1-imidazolyl, 1H-benzotriazolyloxy, 1H-benzotriazolyl or O-SO2-R7Wherein R is7Having the formula R2In the meaning defined in (1) and R2And R7Are the same or different, or
N(R8)SO2R9Wherein R is8Is carbonyl and R9Is unsubstituted or substituted phenyl, and R8And RdEither bonded to each other or not bonded to each other,
wherein the reaction is carried out in
An imidazole base substituted in position 1, or
-in the presence of a base mixture comprising at least one imidazole base substituted in position 1.
Heteroaryl groups falling under formula (1) under the definition of Q include in particular 1, 3, 5-triazin-2-yl.
The N-sulfonyl-substituted 3-triazinyl oxindoles and 3-triazinyl oxindoles used in the process according to the invention are characterized in that, in each case, in addition to the triazinyl group, there is a radical R2Which represent the uniform properties of the compounds of the invention.
During this reaction, the base used does not decompose and release hydrogen (H) in the presence of water2) As for example in the case of sodium hydride.
Transformation of
Furthermore, it was unexpected that the particular imidazole base substituted in position 1 significantly improved the selectivity of the N-sulfonylation compared to the O-sulfonylation of oxindoles with a six-membered heteroaryl group in position 3. This is especially true for obtaining N-sulfonyl substituted 3-triazinyl oxindoles.
It has been shown to be a particular advantage of the use of imidazole bases in connection with the process of the present invention that the bases are capable of catalyzing the complete or partial conversion of an O-sulfonylated heteroaryl-substituted oxindole (D) or other intermediate formed during the reaction as a major or minor component to obtain the desired corresponding N-sulfonylated oxindole (C).
The conversion for 3-triazinyloxyindole is illustrated by scheme 3 and tables 1 and 2 and demonstrated by example 1, variation B.
Scheme 3-conversion during sulfonylation of 3-triazinyl oxindoles:
Figure BDA0000369980320000081
conversion of the O-sulfonylated 3-triazinylooxindole (D) formed to give the desired N-sulfonylated 3-triazinylooxindole (C) or
Directly, i.e. the desired N-sulfonylated 3-triazinyloxyindole (C) is formed directly (example 1, variant B), or
Indirectly, i.e. after the inversion (back-formation) of the starting compound (a), the desired N-sulfonylated 3-triazinyloxyindole (C) is formed.
To demonstrate the conversion of the O-sulfonylated 3-triazinyl oxindole (D) to give the desired N-sulfonylated 3-triazinyl oxindole (C), a mixture consisting of 62% of the O-sulfonylated 3-triazinyl oxindole (D) and 30% of the N-sulfonylated 3-triazinyl oxindole (C) was first isolated. (the fraction of compound A, C, D in the total mixture was determined by HPLC.)
Half of the separated mixture was reacted with the imidazole base 1-methyl-1H-imidazole in the absence of sulfonylating agent difluoromethanesulfonyl chloride (B) (see table 1).
For comparison, the other half of the separated mixture comprising 62% of O-sulfonylated 3-triazinyl oxindole (D) and 30% of N-sulfonylated 3-triazinyl oxindole (C) was stirred at 0 ℃ in the absence of 1-methyl-1H-imidazole and in the absence of the sulfonylating agent difluoromethanesulfonyl chloride (B) (see Table 2).
TABLE 1 (after addition of 1-methyl-1H-imidazole)
Figure BDA0000369980320000091
The results summarized in Table 1 indicate that in the presence of 1-methyl-1H-imidazole, the conversion of O-sulfonylated 3-triazinyl oxindole (D) occurs to obtain the desired N-sulfonylated 3-triazinyl oxindole (C).
The required content of N-sulfonylated 3-triazinyl oxindole (C) increases from 30% to 58%, i.e. the imidazole-catalyzed conversion leads to almost a doubling of the N-sulfonylated 3-triazinyl oxindole (C).
TABLE 2 (without addition of 1-methyl-1H-imidazole)
The results summarized in Table 2 show that the desired conversion of the O-sulfonylated 3-triazinyl oxindole (D) to give the desired N-sulfonylated 3-triazinyl oxindole (C) does not occur without the addition of 1-methyl-1H-imidazole.
Other names used above and below are explained in general terms with respect to the compounds of the invention. This is familiar to the person skilled in the art and has the following explained meanings:
reference in this application to "3-triazinyloxyindole" is intended to mean one of the compounds encompassed by formula (1-1).
3-triazinyloxyindole (1-1) preferably used as a starting material
Figure BDA0000369980320000101
Wherein the radical R1aTo R1d、R3、R4And R5Having the meaning as defined above, can be prepared using methods known to those skilled in the art.
The "sulfonyl compound" mentioned in the present application means one of the compounds included in the formula (2).
In the compound of formula (2), R2And X has the meaning defined above. The sulfonyl compound (2) used as a starting material is known and can be prepared using methods known to those skilled in the art.
Reference in the present application to a "tertiary amine base" is intended to mean one of the compounds encompassed by formula (4),
Figure BDA0000369980320000103
wherein
R10a、R10bAnd R10cIndependently of one another, branched or unbranched (C)1-C6) -alkyl and a substituent R in a non-terminal position10a、R10bAnd R10cAt least one of which comprises a further heteroatom such as oxygen or sulphur or a group NR10dWherein R is10dIs (C)1-C6) -alkyl, or
R10bAnd R10cBonded to each other as a three-to ten-membered ring and which may contain at least one further heteroatom such as oxygen or sulphur or a group NR10dWherein R is10dIs (C)1-C6) -alkyl, or R10a、R10bAnd R10cTogether form a bicyclic ring in which the nitrogen atom present in formula (4) forms a bridgehead atom, the other bridgehead atom may be carbon or nitrogen, if the other bridgehead atom is carbon, one or both rings also contain at least one other heteroatom such as oxygen or sulphur or a group NR10dWherein R is10dIs (C)1-C6) Alkyl groups, and the ring atoms may also be bonded by double bonds.
If the compound of formula (4) contains more than one heteroatom, these heteroatoms may not be directly adjacent to one another.
Reference to "substituted pyridine base" in the present application means one of the compounds encompassed by formula (5),
Figure BDA0000369980320000111
wherein,
R11a、R11b、R11c、R11dand R11eIndependently of one another, hydrogen, methyl, ethyl, propyl or isopropyl and a substituent R11a、R11b、R11c、R11dAnd R11eAt least one of which is not hydrogen.
The name "halogen" means, for example, fluorine, chlorine, bromine or iodine. If the name is used for a group, "halogen" means, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
Alkyl means a straight or branched open chain, saturated hydrocarbon group.
Expression "(C)1-C4) By alkyl is meant the shorthand expression of an alkyl group having 1 to 4 carbon atoms corresponding to a given range of carbon atoms, i.e. including the groups methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methylpropyl or tert-butyl. General alkyl radicals having a relatively large defined range of carbon atoms, e.g. (C)1-C6) Alkyl "also correspondingly includes straight-chain or branched alkyl having a greater number of carbon atoms, i.e. according to this example also alkyl having 5 and 6 carbon atoms.
Cycloalkyl means carbocyclic, saturated ring systems preferably having 3 to 8 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In the case of optionally substituted cycloalkyl, ring systems having substituents are included, in which case substituents having a double bond on the cycloalkyl are also included, for example alkylene groups such as methylene.
In the case of optionally substituted cycloalkyl, polycycloaliphatic systems also include, for example, bicyclo [1.1.0] but-1-yl, bicyclo [1.1.0] but-2-yl, bicyclo [2.1.0] pent-1-yl, bicyclo [2.1.0] pent-2-yl, bicyclo [2.1.0] pent-5-yl, bicyclo [2.2] hept-2-yl (norbornyl), adamantan-1-yl and adamantan-2-yl.
In the case of substituted cycloalkyl groups, spirocyclic aliphatic systems also include, for example, spiro [2.2] pent-1-yl, spiro [2.3] hex-4-yl, 3-spiro [2.3] hex-5-yl.
Aryl means mono-, bi-or polycyclic aromatic systems preferably having 6 to 14, in particular 6 to 10, ring carbon atoms, for example phenyl, naphthyl, anthryl, phenanthryl and the like, preferably phenyl.
The term "optionally substituted aryl" also includes polycyclic systems such as tetralinyl, indenyl, indanyl, fluorenyl, biphenyl, wherein the bonding site is on an aromatic system.
From a system perspective, the term "optionally substituted phenyl" also typically includes aryl groups.
Alkoxy means an alkyl group bonded through one oxygen atom, alkenyloxy means an alkenyl group bonded through one oxygen atom, alkynyloxy means an alkynyl group bonded through one oxygen atom, cycloalkoxy means a cycloalkyl group bonded through one oxygen atom and cycloalkenyloxy means a cycloalkenyl group bonded through one oxygen atom.
Alkylthio means an alkyl group bonded through one sulfur atom, alkenylthio means an alkenyl group bonded through one sulfur atom, alkynylthio means an alkynyl group bonded through one sulfur atom, cycloalkylthio means a cycloalkyl group bonded through one sulfur atom and cycloalkenylthio means a cycloalkenyl group bonded through one sulfur atom.
Haloalkyl, haloalkenyl and haloalkynyl each mean alkyl, alkenyl or alkynyl which are partially or completely substituted by the same or different halogen atoms, for example monohaloalkyl such as CH2CH2Cl、CH2CH2F、CHClCH3、CHFCH3、CH2Cl、CH2F; perhaloalkyl radicals such as CCl3Or CF3Or CF2CF3(ii) a Polyhaloalkyl radicals such as CHF2、CH2F、CH2CHFCl、CHCl2、CF2CF2H、CH2CF3(ii) a Haloalkoxy groups such as OCF3、OCHF2、OCH2F、OCF2CF3、OCH2CF3And OCH2CH2Cl; the same applies to haloalkenyl and other groups substituted by halogen.
Unless otherwise defined, the definition "substituted by one or more groups" means one or more groups which are the same or different independently of each other, wherein two or more groups on one ring as the basic body may form one or more rings.
Substituted radicals, such as substituted alkyl, cycloalkyl, cycloalkenyl, aryl, phenyl, benzyl, heterocyclyl and heteroaryl, mean, for example, substituted radicals which derive from unsubstituted base bodies, where these substituents are, for example, one or more, in particular 1, 2 or 3, groups selected from the following: halogen, alkoxy, alkylthio, hydroxyl, amino, nitro, carboxyl or a group corresponding to carboxyl, cyano, isocyano, azido, alkoxycarbonyl, alkylcarbonyl, formyl, carbamoyl, mono-and dialkylaminocarbonyl, substituted amino (for example acylamino, mono-and dialkylamino), trialkylsilyl and optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, where the last-mentioned ring groups may each also be bonded, as specifically indicated for alkyl, via heteroatoms or divalent functional groups, and alkylsulfinyl (including the two enantiomers of alkylsulfinyl), alkylsulfonyl, alkylphosphinyl, alkylphosphonyl, and also, for cyclic groups (═ cyclics "), alkyl, haloalkyl, alkylthioalkyl, alkylphosphono, Alkoxyalkyl, optionally substituted mono-and dialkylaminoalkyl and hydroxyalkyl.
In the term "substituted group", e.g., substituted alkyl and the like, in addition to the specified saturated hydrocarbon-containing group, also include the corresponding unsaturated aliphatic and aromatic groups, e.g., optionally substituted alkenyl, alkynyl, alkenyloxy, alkynyloxy, alkenylthio, alkynylthio, alkenyloxycarbonyl, alkynyloxycarbonyl, alkenylcarbonyl, alkynylcarbonyl, mono-and dialkenylaminocarbonyl, mono-and dialkynylaminocarbonyl, mono-and dialkenylamino, mono-and dialkynylamino, trienylsilyl, trialkynylsilyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, phenyl, phenoxy and the like, as substituents. For substituted cyclic groups having an aliphatic moiety in the ring, ring systems having substituents doubly bonded to the ring (i.e., substituted with alkylene (e.g., methylene or ethylene) or oxo, imino, or substituted imino) are also included.
The substituted or unsubstituted radicals may be branched or unbranched in each case. Thus, for example, referred to as "C4The radical-alkyl "including, unbranched butyl, and all other C4Isomers, including t-butyl.
If two or more radicals form one or more rings, they may be carbocyclic, heterocyclic, saturated, partially saturated, unsaturated, and, for example, aromatic and optionally further substituted. The fused rings are preferably 5-or 6-membered rings, particularly preferably benzo fused rings.
In a preferred embodiment, R2Is (C)1-C6) -alkyl or (C)3-C7) Cycloalkyl, wherein alkyl or cycloalkyl is fully or partially substituted by fluorine, and excluding
-R1aIs fluorine and
-R2compounds of formula (3-1) which are 2, 2-difluoroethyl or 1, 1, 1-trifluoroethyl, since the formation of these particular compounds cannot be demonstrated under the reaction conditions described in the present application. However, the fact is not excluded that these compounds can be prepared, for example, by varying the composition of the base mixture, or by varying the main reaction temperature or pressure during the reaction.
In the preferred embodiment described above, it is preferred that,
R4and R5Independently of one another each is
The presence of hydrogen in the presence of hydrogen,
(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C1-C6) -alkoxy, wherein alkoxy is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group.
In another preferred embodiment, R3H. In this case, the compounds of the formula (3-1) may be present in whole or in part as enol tautomers or as salts (3-1a),
Figure BDA0000369980320000141
wherein
R1aTo R1dAnd R2、R4And R5Have the meaning as defined above and
m is Li, Na, K, Cs, Ba, Mg, Ca, Zn or N (R)c)4Wherein R iscH or (C)1-C6) -alkyl, and a counterion M+The number of (3-1a) is determined by the specific charge so that the compound of formula (3-1a) is generally neutral.
In a preferred embodiment, difluoromethanesulfonyl chloride is used as sulfonylating agent, i.e. R2Is difluoromethyl.
The imidazole base used in the present invention is preferably an imidazole base
-1-(C1-C6) -an alkyl-1H-imidazole,
-1-(C1-C7) -cycloalkyl-1H-imidazole,
-1-benzyl-1H-imidazole,
-1-aryl-1H-imidazoles,
-1-heteroaryl-1H-imidazole, or
-mixtures comprising at least two specifically named imidazole bases substituted in position 1.
The imidazole base is particularly preferably 1-methyl-1H-imidazole, 1-butyl-1H-imidazole or 1-benzyl-1H-imidazole, which may be used individually or in mixtures, very preferably 1-methyl-1H-imidazole is used.
These bases have the advantage, compared with other bases, for example the bases described in the prior art, such as sodium hydride or potassium tert-butoxide, that they do not generate equimolar amounts of hydrogen or decompose on contact with water and are therefore suitable for use on an industrial scale.
The tertiary amine base or pyridine base substituted therewith does not lead to an N-sulfonylation of the starting material. For example, it is shown that during the sulfonylation reaction using trifluoromethanesulfonic anhydride and 1-methyl-1H-imidazole as base, the N-sulfonylation product is formed (example 9), whereas the O-sulfonylation product is preferentially formed using 1, 4-diazabicyclo [2.2.2] octane (DABCO) as base (example 10). The differentiation of the N-and O-sulfonylation can be carried out by measuring the UV absorption of the product. The N-sulfonylated product showed the maximum absorption at 360nm while the O-sulfonylated product did not show the maximum absorption here.
If less than one equivalent of 1-methyl-1H-imidazole is used, based on the 3-triazinyl oxindole used, the yield drops to be expected.
However, it has now surprisingly been found that selective N-sulfonylation of the starting materials is even possible when a mixture consisting of 1-alkyl-1H-imidazole and a cyclic tertiary amine base (e.g. diazabicyclo [2.2.2] octane (DABCO), methylmorpholine, 1-ethylmorpholine, N-dimethylpiperazine or 1, 2-di (dimethylamino) ethane) or a substituted pyridine base (e.g. 5-ethyl-2-methylpyridine) is used, and wherein less than one equivalent of 1-methyl-1H-imidazole based on the 3-triazinyloxindole used is also present (example 1, variant C).
In the context of the present invention, in addition to the imidazole bases substituted in the 1-position, mixtures of different base types are also used, one base type in this case being an imidazole base substituted in the 1-position. Preference is given to alkali mixtures comprising at least one of the following,
-a tertiary amine base, or
-a substituted pyridine base, and
and at least one of the following imidazole bases substituted in position 1
-1-(C1-C6) -an alkyl 1H-imidazole,
-1-cycloalkyl-1H-imidazole,
-1-benzyl-1H-imidazole,
-1-aryl-1H-imidazole, or
-1-heteroaryl-1H-imidazole.
The tertiary amine base used is preferably diazabicyclo [2.2.2] octane (DABCO), 1-methylmorpholine, 1-ethylmorpholine, N-dimethylpiperazine or 1, 2-bis (dimethylamino) ethane.
As substituted pyridine base in admixture with one or more 1-alkyl-1H-imidazoles, preference is given to using 5-ethyl-2-methylpyridine or 3-methylpyridine or a mixture of the two.
An important aspect relates to the choice of solvent in which the reaction is carried out. The reaction can be carried out in
-polarity, or
In a nonpolar solvent, or in
-in a mixture of polar or non-polar solvents.
Nonpolar solvents which can be used are
Aromatic compounds, in particular toluene, xylene or chlorobenzene.
Polar organic solvents which can be used are
Haloalkanes, in particular dichloromethane or dichloroethane; or
Ketones, in particular butanone, 2-methylbutanone;
nitriles, in particular acetonitrile, butyronitrile, isobutyronitrile;
ethers, in particular dioxane, 2-methyltetrahydrofuran, tert-butyl methyl ether, cyclopropyl methyl ether, dimethoxyethane or tetrahydrofuran; or
Esters, in particular ethyl acetate, n-butyl acetate or isopropyl acetate.
The specifically named polar solvents can be used as such or in admixture with other solvents, preferably with other polar organic solvents.
It is particularly preferred to carry out the process using methylene chloride, 2-methyltetrahydrofuran or ethyl acetate as solvent or using a mixture comprising at least one of the abovementioned particularly preferred solvents.
The process according to the invention for preparing the compounds of formula (3) is based on the fact that: 3-triazinyloxyindole (1 equivalent) is reacted with a sulfonyl compound and an imidazole base, or a mixture comprising an imidazole base, in a suitable solvent. Here, the sulfonyl compound is used in an equimolar amount or in an excess (1.0 to 6 equivalents, preferably 1.2 to 2 equivalents). The bases, either alone or as a mixture of two or more bases, are also used in equimolar amounts or in excess (1.0 to 7 equivalents, preferably 1.4 to 2.5 equivalents).
The addition of the reactants can be carried out in one or more portions over a period of up to 24 hours, preferably up to 6 hours, in particular from 0.05 to 6 hours.
The reaction temperature for the sulfonylation is in the range of-100 ℃ to 50 ℃, especially-20 ℃ to +10 ℃.
The reaction may optionally be carried out under pressure.
For good product yields, it is advantageous first to add the 3-triazinyloxyindole as starting material with the base (total or partial amount) in a suitable solvent and then to add the sulfonyl compound in one or more portions and optionally further amounts of the same base or of a further base or of a mixture of different bases.
An addition variant involves adding the 3-triazinyloxyindole and the sulfonyl compound as starting materials to a suitable solvent and then adding the base or a mixture of different bases in one or more portions. Alternatively, the 3-triazinyloxyindole may be added in one or more portions to the initial charge of sulfonyl compound and base.
It is within the scope of the present invention to add the 3-triazinyloxyindole as a salt to the reaction mixture. In this case, optionally smaller amounts of base may be used.
All reactants may be added to the reaction mixture in pure form or premixed with each other or dissolved or suspended in a solvent or solvent mixture. It is possible to add other solvents during the reaction to promote better mixing of the reactants.
Depending on the reaction conditions used, the poststirring time after addition of all reactants is in the range of up to 96 hours, in particular from 0.05 to 24 hours.
Especially when R is3The post-stirring time is advantageous, since especially in this case, during the sulfonylation reaction, an O-sulfonylation product can also be formed at least in part, which in turn, as described above, is converted into the desired N-sulfonylation product of the formula (3) under the influence of the imidazole base and/or can be reacted further.
The work-up and isolation of the desired product of formula (3) can be carried out in different ways and depends, for example, on the choice of solvent or on whether the product is a solid or a liquid.
The reaction mixture containing the solid product of formula (3) or (3-1) was filtered. The solid product obtained in this way can be washed with suitable solvents and/or acid solutions.
Furthermore, the invention provides that another higher boiling solvent, in which the product has a lower solubility, is added to the reaction mixture comprising the product of formula (3), and then the low boiling solvent is distilled off completely or partly. The product present as a solid is then filtered off and can be washed with suitable solvents and/or acid solutions.
Furthermore, it is within the scope of the invention to extract the product obtained after filtration and optional washing from a suitable solvent or a mixture of two or more solvents by stirring to obtain a higher purity.
Further, the present invention provides that the product of formula (3), or (3-1) or a salt thereof (3-1a) present in the reaction mixture is further reacted without isolation to obtain a continuous product.
The present invention also provides N-sulfonyl substituted 3-triazinyl oxindoles of formula (3-1) or salts thereof (3-1a), regardless of the preparative nature of these compounds.
Thus included are N-sulfonyl substituted 3-triazinyl oxindoles of formula (3-1)
Figure BDA0000369980320000181
And salts thereof (3-1a)
Wherein, in each case,
R1ato R1dIndependently of one another, selected from: hydrogen, fluorine, chlorine, bromine, iodine, and is selected from
(C1-C6) -an alkyl group, wherein the alkyl group is branched or unbranched and is unsubstituted or substituted by one or morePlural are selected from fluorine, chlorine and (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C3-C7) -cycloalkyl, wherein cycloalkyl is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)3-C7) -cycloalkyl or (C)1-C4) -a substituent of an alkoxy group,
(C1-C6) -alkoxy, wherein alkoxy is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C3-C7) -cycloalkoxy, wherein cycloalkoxy is unsubstituted or substituted with one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
(C1-C6) Alkylthio, wherein alkylthio is branched or unbranched and is unsubstituted or substituted by one or more substituents selected from the group consisting of fluorine, chlorine, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
(C3-C7) Cycloalkylthio, wherein cycloalkylthio is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)1-C4) -substituent substitution of alkoxy, and
phenyl or 1-naphthyl or 2-naphthyl or a five-or six-membered heteroaromatic ring having 1 to 2 heteroatoms, wherein the heteroatoms are independently of one another selected from O or N and wherein aryl or heteroaryl is unsubstituted or is substituted by one or more groups selected from fluorine, chlorine, bromine, iodine, (C)1-C4) Alkyl radicals, (C)1-C4) -alkoxy or (C)3-C7) -cycloalkyl or (C)1-C4) Substitutents of alkylthioGeneration, and
R2is composed of
Methyl, wherein the methyl is completely or partially substituted by fluorine, or
(C3-C7) Cycloalkyl, wherein cycloalkyl is fully or partially substituted by fluorine,
R3is composed of
Hydrogen, or
(C1-C6) -an alkyl group, wherein the alkyl group is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluorine, chlorine, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C1-C6) Alkylthio, wherein alkylthio is unsubstituted or substituted by one or more substituents selected from the group consisting of fluorine, chlorine, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
R4and R5Independently of one another each is
The presence of hydrogen in the presence of hydrogen,
(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C1-C6) -alkoxy, wherein alkoxy is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
wherein, in the salt of formula (3-1a), M is Li, Na, K, Cs, Ba, Mg, Ca, Zn or N (R)c)4Wherein R iscH or (C)1-C6) -alkyl, and wherein the counterion M+Is determined by the specific charge to form a generally neutral compound of formula (3-1 a).
All stereoisomers, rotamers, tautomers and polymorphs, if applicable, are also encompassed by formulas (3-1) and (3-1 a).
Particular preference is given to compounds of the formula (3-1) or salts of the formula (3-1a), in which
R1aTo R1dIndependently of one another, from hydrogen, fluorine, chlorine, and from
(C1-C6) -an alkyl group, wherein the alkyl group is branched or unbranched, or
(C1-C6) -an alkoxy group, wherein the alkoxy group is branched or unbranched, and
R2is a difluoromethyl group or a trifluoromethyl group,
R3is a hydrogen atom, and is,
R4and R5Independently of one another each is
(C1-C4) -an alkyl group, wherein the alkyl group is branched or unbranched,
(C1-C4) -alkoxy, wherein the alkoxy is branched or unbranched,
wherein, in the salt of formula (3-1a), M is Na and K.
Very particular preference is given to compounds of the formula (3-1) or salts thereof of the formula (3-1a), in which
R1aTo R1dIndependently of one another, from hydrogen, fluorine, chlorine, methoxy, and
R2is a difluoromethyl group,
R3is hydrogen, and
R4and R5Independently of one another, are each methoxy.
Most preferred are compounds of formula (3-1) or a salt thereof of formula (3-1a), wherein R1aTo R1dIndependently of one another, from hydrogen and fluorine.
The invention also provides the use of the compounds of the formula (3) or (3-1) or their salts (3-1a) prepared according to the invention as active ingredients in medicine or agriculture, and the use of the specifically named compounds for preparing active ingredients for agriculture or for preparing fine chemicals for agriculture and intermediates for the preparation of active ingredients.
Particularly preferred is the use as fungicide or herbicide and/or the use for the preparation of fungicides and herbicides and/or the use of the specifically specified compounds as intermediates for the preparation of fungicides and herbicides.
Very particular preference is given to the use of the specifically specified compounds as herbicides and/or the use for preparing herbicides.
The N-sulfonyl-substituted 3-triazinyl oxindoles of the formulae (3-1) and (3-1a) and also the N-sulfonyl-substituted 3-heteroaryloxindoles of the formula (3) which are prepared by the process according to the invention are suitable as intermediates for the preparation of fine chemicals and active ingredients for agriculture.
For them, it is possible to prepare N-alkyl-N- [2- (1, 3, 5-triazin-2-ylcarbonyl) phenyl ] alkanesulfonamides of formula (4-1) -see scheme 4 below-whose herbicidal activity (see WO2007/031208A2) and fungicidal activity (see WO2006/008159A1) are described in the publications cited in both.
The compound of formula (3) is an N-sulfonyl substituted 3-triazinyloxyindole.
In the following scheme 4, formula (3-1) represents an N-sulfonyl substituted 3-triazinyloxyindole.
Scheme 4 shows a novel multistage synthesis according to which, starting from 3- (alkylsulfanyl) -1, 3-dihydro-2H-indol-2-one of formula (7-1), N-alkyl-N- [2- (1, 3, 5-triazin-2-ylcarbonyl) phenyl ] alkanesulfonamides of formula (4-1) can be prepared in an integrated five-step reaction, the herbicidal activity (see WO2007/031208a2) and fungicidal activity (see WO2006/008159a1) of which have long been known.
Scheme 4: multistep process for preparing N-alkyl-N- [2- (1, 3, 5-triazin-2-ylcarbonyl) phenyl ] alkanesulfonamides (4-1), especially herbicidal ketones, suitable for crop protection
Figure BDA0000369980320000211
The multi-step process of scheme 4 for the preparation of N-alkyl-N- [2- (1, 3, 5-triazin-2-ylcarbonyl) phenyl ] alkanesulfonamides (4-1) consists of the following steps:
-subjecting substituted or unsubstituted 3- (alkylsulfanyl) -1, 3-dihydro-2H-indol-2-one (7-1) to a reduction reaction to give substituted or unsubstituted 1, 3-dihydro-2H-indol-2-one (6-1). This process is feasible on an industrial scale and is described in the patent application with the application number EP 10162381.7.
-arylating a substituted or unsubstituted 1, 3-dihydro-2H-indol-2-one (6-1) to give a triazinyl-substituted oxindole (5-1). This process is feasible on an industrial scale and is described in the patent application with the application number EP 10196205.8.
-sulfonylation of the triazinyl-substituted oxindole (5-1) according to the sulfonylation process of the present invention to give the N-sulfonyl-substituted 3-triazinyl oxindole (3-1).
-subjecting the N-sulfonyl substituted 3-triazinyloxyindole (3-1) to an oxidative ring-opening reaction to give the 2- (triazinylcarbonyl) sulfonanilide (1-1). This process is feasible on an industrial scale and is described in the patent application with the application number DE 102011086382.6.
-alkylating the 2- (triazinylcarbonyl) sulfonanilide (1-1) to give N-alkyl-N- [2- (1, 3, 5-triazin-2-ylcarbonyl) phenyl ] alkanesulfonamide (4-1). This process is described in patent application No. WO2006/008159A 1.
In contrast to previously known processes for the preparation of N-alkyl-N- [2- (1, 3, 5-triazin-2-ylcarbonyl) phenyl ] alkanesulfonamides (4-1) and 2- (triazinylcarbonyl) sulfonanilides (1-1), the multistep process shown in scheme 4 is worth mentioning that oxindole compounds are used as starting materials and/or as intermediates. This has the advantage over previously known processes that the process can be carried out on an industrial scale and at the same time high yields can be achieved.
The manner in which the process summarized in scheme 4 was carried out is disclosed in detail below. The reduction reaction in scheme 4 involving the first reaction step in the overall five-step reaction is treated as a separate initial stage B) as follows. The process A) described in detail below therefore only involves the steps of arylation, sulfonylation, oxidation and alkylation.
A) Process for the preparation of N-alkyl-N- [2- (1, 3, 5-triazin-2-ylcarbonyl) phenyl ] alkanesulfonamides of formula (4-1)
R1aTo R1dIndependently of one another, from hydrogen, fluorine, chlorine, bromine, iodine, and from
(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C3-C7) -cycloalkyl, wherein cycloalkyl is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)3-C7) -cycloalkyl or (C)1-C4) -a substituent of an alkoxy group,
(C1-C6) -alkoxy, wherein alkoxy is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C3-C7) -cycloalkoxy, wherein cycloalkoxy is unsubstituted or substituted with one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
(C1-C6) Alkylthio, wherein alkylthio is unsubstituted or substituted by one or more substituents selected from the group consisting of fluorine, chlorine, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
(C3-C7) Cycloalkylthio, wherein cycloalkylthio is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)1-C4) -substituent substitution of alkoxy, and
phenyl or 1-naphthyl or 2-naphthyl or a five-or six-membered heteroaromatic ring having 1 to 2 heteroatoms, wherein the heteroatoms are independently of one another selected from O or N, and wherein aryl or heteroaryl is unsubstituted or is substituted by one or more groups selected from fluorine, chlorine, bromine, iodine, (C)1-C4) Alkyl radicals, (C)1-C4) -alkoxy or (C)3-C7) -cycloalkyl or (C)1-C4) -substituent substitution of alkylthio, and
R2is composed of
(C1-C6) -alkyl, wherein alkyl is unsubstituted or fully or partially substituted by fluorine, or
(C3-C7) Cycloalkyl, wherein cycloalkyl is unsubstituted or fully or partially substituted by fluorine,
R4and R5Independently of one another each is
The presence of hydrogen in the presence of hydrogen,
(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C1-C6) -alkoxy, wherein alkoxy is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
R8is composed of
(C1-C6) Alkyl, wherein alkyl is unsubstituted or fully or partially substituted by fluorine,
(C1-C6) -cycloalkyl, (C)1-C6) -alkenyl or (C)1-C6) Alkoxyalkyl, in which each specifically named group is unsubstituted or completely or partially substituted by fluorine,
wherein
1, 3-dihydro-2H-indol-2-ones of formula (6-1)
Figure BDA0000369980320000241
R1aTo R1dHas the meaning as defined in formula (4-1),
R3is hydrogen, and
R7is a hydrogen atom, and is,
in a first step by
Arylation to give triazinyl-substituted oxindoles of the formula (5-1)
R1aTo R1dAnd R4And R5Has the meaning as defined in formula (4-1) and R3And R7Has the meaning as defined in formula (6-1),
the arylated product of the formula (5-1) is then passed in a second step
-sulfonylation to give an N-sulfonyl substituted 3-triazinyl oxindole of formula (3-1)
Figure BDA0000369980320000243
R1aTo R1d，R2And R4And R5Has the meaning as defined in formula (4-1) and R3Has the meaning as defined in formula (6-1),
the sulfonylated product of formula (3-1) is then passed in a third step
Oxidative ring-opening reaction to give 2- (triazinylcarbonyl) sulfonanilides of the formula (1-1)
Figure BDA0000369980320000251
R1aTo R1d，R2And R4And R5Has the meaning as defined in formula (4-1),
the oxidation product of the formula (1-1) is then passed in a fourth step
-alkylation reaction to give N-alkyl-N- [2- (1, 3, 5-triazin-2-ylcarbonyl) phenyl ] alkanesulphonamides of formula (4-1)
Figure BDA0000369980320000252
R1aTo R1d，R2、R4、R5And R8Has the meaning as defined for the above formula (4-1),
wherein the alkylating agent used is
-X-R8Wherein X is chlorine, bromine or iodine, and R8Has the meaning as defined for the above formula (4-1), or
-(R8)2SO4Wherein R is8Has the meaning as defined for the above formula (4-1).
The sulfonylation reaction is carried out in accordance with the teachings of the present invention, i.e., in the presence of
An imidazole base substituted in position 1, or
-a base mixture comprising at least one imidazole base substituted in position 1.
Particularly preferred imidazole bases are 1-methyl-1H-imidazole, 1-butyl-1H-imidazole or 1-benzyl-1H-imidazole, which may be used alone or in mixtures, very particularly preferably 1-methyl-1H-imidazole.
B) A process for the preparation of N-alkyl-N- [2- (1, 3, 5-triazin-2-ylcarbonyl) phenyl ] alkanesulfonamides of formula (4-1), wherein the compound of formula (6-1) used as starting material is prepared in a preliminary step, starting from 3- (alkylsulfanyl) -1, 3-dihydro-2H-indol-2-one of formula (7-1)
Figure BDA0000369980320000261
R1aTo R1dHas the meaning as defined in formula (4-1),
R3is a hydrogen atom, and is,
R7is hydrogen, and
R6is unsubstituted or is substituted by (C)1-C14) Alkyl radicals, (C)3-C7) -cycloalkyl, benzyl or CH2-C(O)O-(C1-C6) -an alkyl substitution,
by passing
-reduction conversion to 1, 3-dihydro-2H-indol-2-one (6-1)
Figure BDA0000369980320000262
Wherein
R1aTo R1d，R3And R7Has the meaning as defined in formula (7-1).
When the reduction reaction is carried out in the presence of a catalyst,
a) the compound of formula (7-1) is dissolved or suspended in a polar solvent,
b) adding a sulfur-containing salt to the solution or suspension, and
c) the reaction mixture is heated to reflux at a temperature most consistent with the boiling point of the polar solvent.
Particularly preferred sulfur-containing salts are sodium salts selected from sodium bisulfite, sodium sulfite, sodium dithionite and sodium thiosulfate.
As already mentioned above, the herbicidal effect (see WO2007/031208A2) and fungicidal effect (see WO2006/008159A1) of N-alkyl-N- [2- (1, 3, 5-triazin-2-ylcarbonyl) phenyl ] alkanesulfonamides of the formula (4-1) have long been known.
Thus, scheme 4 and the manner in which methods A) and B) are carried out demonstrate that the heteroaryl-substituted oxindoles of the formula (3), and the triazinyl-substituted oxindoles of the formula (3-1) and their salts (3-1a) are suitable as intermediates for the preparation of crop protection compositions, in particular herbicides and fungicides.
Most preferred is the use of a compound of formula (3) or (3-1) or a salt thereof (3-1a) as an intermediate for the preparation of N-alkyl-N- [2- (1, 3, 5-triazin-2-ylcarbonyl) phenyl ] alkanesulfonamides.
Examples
The following examples illustrate the present invention in more detail, but the subject matter thereof is not limited to these examples.
In the following examples, the quantitative data are based on weight unless otherwise specifically defined (in the present specification,% bywt. is used analogously thereto). For the metering units, physical parameters, etc., the customary abbreviations are used, for example h ═ hour, m.p. ═ melting point, l ═ liter, ml ═ milliliter, g ═ gram, min ═ minute, in vacuo ("in vacuum") ("in reduced pressure"), theoretical values are theoretical percent yields, RT ═ room temperature, eq.
The coupling pattern in the NMR spectrum is described in its presentation form.
Unless otherwise indicated, parts are given as relative area percentages in HPLC analysis.
Percentages in LCMS analysis refer to the relative parts of each component in the chromatogram.
Example 1:
preparation of 1- [ (difluoromethyl) sulfonyl ] -3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1, 3-dihydro-2H-indol-2-one
Figure BDA0000369980320000271
Variation a:
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1, 3-dihydro-2H-indol-2-one (95.7g) and 1-methyl-1H-imidazole (53.1g) were added as starting materials to 1120ml of ethyl acetate and then cooled to 0 ℃ under nitrogen. Difluoromethanesulfonyl chloride (73.7g) was added dropwise at 0 ℃ to 5 ℃ over 30 minutes with vigorous stirring, and the mixture was post-stirred for 3.5 hours. Additional difluoromethanesulfonyl chloride (4.9g) was added to the reaction mixture and stirred for 1.5 hours. The reaction mixture was admixed with 500ml of water and mixed vigorously. Most of the organic solvent was distilled off under vacuum and the residue was filtered. The solid product is washed twice with 250ml of water, extracted with 400ml of ethyl acetate/heptane (1: 1) with stirring, filtered and washed with 100ml of ethyl acetate/heptane (1: 1). The title compound was obtained as a solid with a purity of 96% relative to standard (123.1g, 91% of theory). The N-sulfonylation of the product was confirmed by UV absorption (maximum at 360 nm).
LC-MS：M+H＝405(95％)。
1H-NMR(400MHz，CDCl3): δ (ppm) is 12.6(s, width, 1H), 7.83(d, 1H), 7.20(dt, 1H), 6.93(dd, 1H), 6.70(t, 1H), 4.21(s, 3H), 4.16(s, 3H).
Variation B:
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1, 3-dihydro-2H-indol-2-one (100g) and 1-methyl-1H-imidazole (44.8g) were added as initial charge to 670ml of dichloromethane and then cooled to-10 ℃ under nitrogen. Difluoromethanesulfonyl chloride (72.6g) was added dropwise over 35 minutes at-12 ℃ to-3 ℃ with vigorous stirring, and the mixture was post-stirred for 4.5 hours at-10 ℃ to-5 ℃. HPLC detection after one and 3 hours shows the presence of the O-sulfonylated starting material produced as an intermediate, which at the end of the reaction is almost completely converted into the desired product. The reaction mixture was admixed with 500ml of water and mixed vigorously. Most of the organic solvent was distilled off under vacuum and the residue was filtered. The solid product was washed twice with 100ml of 5% strength hydrochloric acid and twice with 100ml of water and then dried in a vacuum drying oven. The title compound was obtained as a solid with 93% purity relative to standard (136g, 93% of theory). The NMR signals of the products correspond to those of the products obtained according to variant A.
Variation C:
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1, 3-dihydro-2H-indol-2-one (10 g; 33mmol) was added as starting material to 40ml of dichloromethane and cooled to-20 ℃. 1-methyl-1H-imidazole (0.84 g; 10mmol) and 4-ethylmorpholine (5.5 g; 47mmol) were added and the reaction mixture was stirred slightly. Difluoromethanesulfonyl chloride (6.2g) was added dropwise at-20 ℃ to-10 ℃ with vigorous stirring, and the mixture was post-stirred at-20 ℃ to-10 ℃ for 3 hours. Then admixed with 50ml of dichloromethane and stirred for one hour thereafter. Difluoromethanesulfonyl chloride (0.5g) was added to the solution, and the mixture was stirred for one hour. The reaction mixture was warmed to room temperature, transferred to a stirring-out flash and admixed with 100ml of water. Most of the organic solvent was distilled off under vacuum and the residue was filtered. The solid product was washed with 50ml of 5% strength hydrochloric acid, water and 2-propanol, respectively, and then dried in a vacuum drying oven. The title compound was obtained as a solid in 98.8% HPLC purity (13.3g, 97% of theory). The NMR signals of the products correspond to those of the products obtained according to variant A.
Variant D (═ comparative example 1D):
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1, 3-dihydro-2H-indol-2-one (3.0g) was added as a starting material to 60ml of tetrahydrofuran and cooled to 0 ℃ before sodium hydride (0.52g, 60% in mineral oil) was added. The reaction mixture was stirred for one hour, difluoromethanesulfonyl chloride (1.7g) was added dropwise at 0 ℃ and the mixture was stirred after 0 ℃ for 12 hours. HPLC analysis detected starting material (72%), desired product (8%) and other components.
Variant E (═ comparative example 1E):
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1, 3-dihydro-2H-indol-2-one (3.0g) was added as a starting material to 60ml of tetrahydrofuran and cooled to-30 ℃ before potassium tert-butoxide (1.26g) was added. The reaction mixture was heated to 0 ℃ over one hour, then cooled to-60 ℃, difluoromethanesulfonyl chloride (1.7g) was added dropwise, then the mixture was slowly warmed to room temperature and stirred for 12 hours afterwards. HPLC analysis detected the starting material (61%), the desired product (6%) and other components.
Variant F (═ comparative example 1F):
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1, 3-dihydro-2H-indol-2-one (3.0g) was added as a starting material to 30ml of dichloromethane and cooled to-15 ℃ before triethylamine (1.86g) was added. The reaction mixture was stirred slightly, difluoromethanesulfonyl chloride (2.2g) was added dropwise, and then the mixture was stirred after-15 to-10 ℃ for 3 hours. The mixture was allowed to stand at room temperature for 15 hours. HPLC analysis detected the starting material (53%), the desired product (approximately 3%) and other components.
Variation G:
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1, 3-dihydro-2H-indol-2-one (3 g; 10mmol) was added as starting material to 50ml of dichloromethane. 1-methyl-1H-imidazole (0.17 g; 2.0mmol) and 5-ethyl-2-methylpyridine (2.0 g; 16mmol) were added and the reaction mixture was cooled to-10 ℃ and stirred slightly. Difluoromethanesulfonyl chloride (2.5g, 16mmol) was added dropwise at-20 ℃ to-5 ℃ with vigorous stirring, followed by stirring at-20 ℃ to-5 ℃ for 7 hours. The reaction mixture was warmed to room temperature, transferred to a stirred flask, and admixed with 30ml of water. Most of the organic solvent was distilled off under vacuum and the residue was filtered. The solid product was washed with 30ml of 5% strength hydrochloric acid, water 2-propanol and then dried in a vacuum drying oven. 94% of solid title compound (3.7g, 84% of theory) are obtained in HPLC purity.
Example 2:
preparation of 1- [ (difluoromethyl) sulfonyl ] -7-fluoro-3- (4-methoxy-6-methyl-1, 3, 5-triazin-2-yl) -1, 3-dihydro-2H-indol-2-one
Figure BDA0000369980320000301
7-fluoro-3- (4-methoxy-6-methyl-1, 3, 5-triazin-2-yl) -1, 3-dihydro-2H-indol-2-one (1.20g) and 1-methyl-1H-imidazole (0.97g) were added as starting materials to 10ml of dichloromethane and then cooled to 0 ℃ under nitrogen. Difluoromethanesulfonyl chloride (1.21g) was added in 2 portions with stirring, and the mixture was warmed to room temperature. After 5 hours, 1-methyl-1H-imidazole (0.32g) and difluoromethanesulfonyl chloride (0.61g) were added and the mixture was stirred for 16 hours. After addition of water and some hydrochloric acid, the solid was filtered off, washed with dichloromethane and water and then dried. The title compound was obtained as a solid in 91% HPLC purity (1.54g, 92% of theory). The N-sulfonylation of the product was confirmed by UV absorption (maximum at 360 nm).
LC-MS：M+H＝389(71％)。
1H-NMR(400MHz，DMSO-D6)：δ(Ppm)＝7.94(d，1H)，7.53(t，1H)，7.29(dt，1H)，7.03(dd，1H)，4.12(s，3H)，2.58(s，3H)。
Example 3:
preparation of 1- [ (difluoromethyl) sulfonyl ] -3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -1, 3-dihydro-2H-indol-2-one
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -1, 3-dihydro-2H-indol-2-one (10g) and 1-methyl-1H-imidazole (5.4g) were added as starting materials to 100ml of dichloromethane and then cooled to-5 ℃ under nitrogen. Difluoromethanesulfonyl chloride (7.03g) was added dropwise over 20 minutes at-5 ℃ to 0 ℃ with stirring, and the mixture was stirred after 2.5 hours at this temperature. The reaction mixture was admixed with 50ml of water and mixed thoroughly. Most of the organic solvent was distilled off under vacuum and the residue was filtered. The solid product was washed with water and acetonitrile and then dried in a vacuum oven. 93% of solid title compound (12.5g, 92% of theory) are obtained in HPLC purity. The N-sulfonylation of the product was confirmed by UV absorption (maximum at 360 nm).
LC-MS：M+H＝387(98％)。
1H-NMR (400MHz, CDCl 3): δ (ppm) is 12.55(s, width, 1H), 7.98(d, 1H), 7.76(d, 1H), 7.23(t, 1H), 7.16(t, 1H), 6.68(t, 1H), 4.22(s, 3H), 4.15(s, 3H).
Example 4:
preparation of 1- [ (difluoromethyl) sulfonyl ] -3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -5-fluoro-1, 3-dihydro-2H-indol-2-one
Figure BDA0000369980320000311
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -5-fluoro-1, 3-dihydro-2H-indol-2-one (50g) and 1-methyl-1H-imidazole (30.5g) were added as initial charge to 430ml of dichloromethane and then cooled to-10 ℃ under nitrogen. A solution of difluoromethanesulfonyl chloride (41.8g) in 70ml of dichloromethane was added dropwise at-15 ℃ to-5 ℃ over 30 minutes with stirring, and the mixture was stirred for 4 hours after-15 ℃ to 0 ℃. To the reaction mixture was added 1-methyl-1H-imidazole (2.7g) and difluoromethanesulfonyl chloride (4.9g) and stirred at 0 ℃ for 2 hours. 300ml of water was added to the reaction mixture under ice-cooling, the mixture was post-stirred for 30 minutes and then most of the organic solvent was distilled off under vacuum. The residue was filtered and the solid product was washed twice with 150ml of water and twice with 40ml of acetonitrile and then dried. The title compound is obtained as a solid with an HPLC purity of 96% (63.9g, 95% of theory). The N-sulfonylation of the product was confirmed by UV absorption (maximum at 360 nm).
LC-MS：M+H＝405(97％)。
1H-NMR(400MHz，CDCl3): δ (ppm) 12.5(s, width, 1H), 7.63-7.72(m, 2H), 6.85(dt, 1H), 6.67(t, 1H), 4.22(s, 3H), 4.17(s, 3H).
Example 5:
preparation of 3- (4, 6-diethoxy-1, 3, 5-triazin-2-yl) -1- [ (difluoromethyl) sulfonyl ] -7-fluoro-1, 3-dihydro-2H-indol-2-one
Figure BDA0000369980320000321
3- (4, 6-diethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1, 3-dihydro-2H-indol-2-one (1.0g) and 1-methyl-1H-imidazole (0.51g) were added as starting materials to 10ml of dichloromethane and then cooled to 0 ℃ under nitrogen. Difluoromethanesulfonyl chloride (0.46g) was added dropwise with stirring, and the mixture was post-stirred at 0 ℃ to 6 ℃ for 2 hours. After addition of 1-methyl-1H-imidazole (0.25g) and difluoromethanesulfonyl chloride (0.23g), the mixture was stirred at 0 ℃ to 10 ℃ for 2 hours. After addition of 5ml of water, the mixture is adjusted to pH 2 with 10% strength hydrochloric acid, the major part of the organic solvent is distilled off under vacuum) and the solid is filtered off, washed with water and heptane and dried. 93% of solid title compound (1.19g, 83% of theory) are obtained in HPLC purity. The N-sulfonylation of the product was confirmed by UV absorption (maximum at 360 nm).
LC-MS：M+H＝433(91％)。
1H-NMR(400MHz，DMSO-D6)：δ(ppm)＝7.86(dd，1H)，7.52(t，1H)，7.22-7.31(m，1H)，7.00(dd，1H)，4.58(q，4H)，.41(t，6H)。
Example 6:
preparation of 1- [ (difluoromethyl) sulfonyl ] -3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -5, 7-difluoro-1, 3-dihydro-2H-indol-2-one
In analogy to example 5, 3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -5, 7-difluoro-1, 3-dihydro-2H-indol-2-one (1.0g), 1-methyl-1H-imidazole (0.74g) and difluoromethanesulfonyl chloride (1.09g) were reacted in 8ml of dichloromethane. For work-up, water was added and stirred, then the solid was filtered off, washed with dilute hydrochloric acid and water and dried. The title compound was obtained as a solid with an HPLC purity of 97% (1.08g, 82% of theory). The N-sulfonylation of the product was confirmed by UV absorption (maximum at 360 nm).
LC-MS：M+H＝423(96％)。
1H-NMR(400MHz，DMSO-D6)：δ(ppm)＝7.64(dd，1H)，7.51(t，1H)，7.00(dt，1H)，4.12(s，6H)。
Example 7:
preparation of 1- [ (difluoromethyl) sulfonyl ] -3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -5-methoxy-1, 3-dihydro-2H-indol-2-one
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -5-methoxy-1, 3-dihydro-2H-indol-2-one (1.0g) and 1-methyl-1H-imidazole (0.51g) were added as starting materials to 8ml of dichloromethane and then cooled to-10 ℃ under nitrogen. Difluoromethanesulfonyl chloride (0.66g) was added dropwise in two portions under stirring and the mixture was then stirred at-5 to-10 ℃ for 2.5 hours. For work-up, water was added and the mixture was stirred, then the solid was filtered off, washed with dilute hydrochloric acid and water and dried. The title compound is obtained as a solid in 99% HPLC purity (0.91g, 70% of theory). The N-sulfonylation of the product was confirmed by UV absorption (maximum at 360 nm).
LC-MS：M+H＝417(100％)。
1H-NMR(400MHz，DMSO-D6)：δ(ppm)＝7.61(d，1H)，7.46(d，1H)，7.44(t，1H)，6.71(dd，1H)，4.11(s，6H)，3.77(s，3H)。
Example 8:
preparation of 1- [ (difluoromethyl) sulfonyl ] -3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-methoxy-1, 3-dihydro-2H-indol-2-one
Figure BDA0000369980320000332
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-methoxy-1, 3-dihydro-2H-indol-2-one (1.0g) and 1-methyl-1H-imidazole (0.47g) were added as starting materials to 8ml of dichloromethane and then cooled to-15 ℃ under nitrogen. Difluoromethanesulfonyl chloride (0.62g) was added dropwise in two portions with stirring, and the mixture was heated to 10 ℃ over 2.5 hours. Cooled to 0 ℃, 1-methyl-1H-imidazole (0.24g) and difluoromethanesulfonyl chloride (0.35g) were added, and then the mixture was heated to room temperature over 3 hours, stirred for 4 hours and then left to stand for 48 hours. For work-up, water was added and the mixture was stirred, then the solid was filtered off, washed with dilute hydrochloric acid and water and dried. 91% of solid title compound (0.52g, 39% of theory) in HPLC purity are obtained. The N-sulfonylation of the product was confirmed by UV absorption (maximum at 360 nm).
LC-MS：M+H＝417(87％)。
1H-NMR(400MHz，DMSO-D6)：δ(ppm)＝7.68(d，1H)，7.46(t，1H)，7.23(t，1H)，6.90(d，1H)，4.11(s，6H)，3.88(s，3H)。
Example 9:
preparation of 3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1- [ (trifluoromethyl) sulfonyl ] -1, 3-dihydro-2H-indol-2-one
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1, 3-dihydro-2H-indol-2-one (1.0g) and 1-methyl-1H-imidazole (1.09g) were added as starting materials to 10ml of dichloromethane and then cooled to 0 ℃ under nitrogen. Trifluoromethanesulfonic anhydride (1.89g) was added in 4 portions with stirring at an internal temperature of 0-10 ℃. The mixture was stirred at a maximum temperature of 15 ℃ for one hour. The mixture was again cooled in an ice bath, water was added, the pH was adjusted to 2 with hydrochloric acid and the phases were separated. The organic phase is washed with water, dried and then concentrated by evaporation. The title compound was obtained as a solid in 68% HPLC purity (1.38g, 67% of theory). The N-sulfonylation of the product was confirmed by UV absorption (maximum at 360 nm).
LC-MS：M+H＝423(35％)。
1H-NMR(400MHz，DMSO-D6)：δ(ppm)＝7.96(d，1H)，7.32(dt，1H)，7.03(dd，1H)，4.12(s，6H)。
Example 10:
preparation of trifluoromethanesulfonic acid 3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1H-indol-2-yl ester
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1, 3-dihydro-2H-indol-2-one (1.0g) and 1, 4-diazabicyclo [2.2.2] octane (0.82g) were added as starting materials to 10ml of dichloromethane and then cooled to-10 ℃ under nitrogen. Triflic anhydride (1.42g) was added dropwise with stirring and the mixture was warmed to room temperature over 4.5 hours. The mixture was allowed to stand for 15 hours. 1, 4-diazabicyclo [2.2.2] octane (0.48g) and trifluoromethanesulfonic anhydride (0.94g) were added, and the mixture was stirred for 5 hours and adjusted to a pH of 1-2 with dilute hydrochloric acid. The solid was filtered off, washed with dichloromethane and water and dried. The title compound was obtained as a solid in 88% HPLC purity (0.45g, 28% of theory). The O-sulfonylation of the product was confirmed by UV absorption (maximum at 360 nm).
LC-MS：M+H＝423(52％)。
1H-NMR(400MHz，DMSO-D6): δ (ppm) H.4(s, width, 1H), 8.37(d, 1H), 7.31(dt, 1H), 7.24(dd, 1H), 4.06(s, 6H).
Example 11(═ comparative example 11):
preparation of 4-methylbenzenesulfonic acid 3-phenyl-1H-indol-2-yl ester
3-Phenyloxindole (1.15g), 4-methylbenzenesulfonyl chloride (1.06g) and sodium carbonate (0.41g) were added as starting materials to 5.5ml of water and 11ml of acetone and heated to 80 ℃ with stirring in a preheated oil bath. After 20 minutes, 5m1 of acetone and 1ml of water were then added and the mixture was heated for a further 30 minutes. The hot solution is filtered, then the solid is washed with 20ml of water/acetone (1: 1) and methanol and dried under vacuum. 0.59g of product of 98% HPLC purity (29% of theory) are obtained. The structural elucidation by NMR confirmed it to be an O-sulfonylated product. Another 0.67g of product of 40% HPLC purity can be isolated by filtration (13% of theory).
LC-MS：M-H＝362(87％)。
1H-NMR(400MHz，DMSO-D6)：δ(ppm)＝10.94(s，1H)，7.90-7.95(m，2H)，7.83(d，1H)，7.40-7.47(m，3H)，7.35(t，1H)，7.22-7.28(m，4H)，7.20(t，1H)，6.76(d，1H)，2.33(s，3H)。
Example 12:
preparation of 1- [ (difluoromethyl) sulfonyl ] -3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-3-methyl-1, 3-dihydro-2H-indol-2-one
Step (a): 3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-3-methyl-1, 3-dihydro-2H-indol-2-one
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1, 3-dihydro-2H-indol-2-one (5.0g) was added as a starting material to 225ml of acetonitrile, sodium hydride (0.73g, 60% in mineral oil) was added and the mixture was stirred until a thick suspension formed. After addition of methyl iodide (7.0g), the mixture was heated to 60 ℃ and stirred at 60 ℃ for 11 hours. Most of the organic solvent was distilled off under vacuum. 2-propanol was added to the partially crystallized residue and the product was filtered off. This gave 93% of solid intermediate (3.46g, 64% of theory) in HPLC purity. The structure can be confirmed by NMR spectrum.
LC-MS：M+H＝305(89％)。
1H-NMR(400MHz，CDCl3)：δ(ppm)＝8.91(s，1H)，6.95-7.03(m，2H)，6.91-6.95(m，1H)，4.02(s，6H)，1.90(s，3H)。
Step (b): 1- [ (difluoromethyl) sulfonyl ] -3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-3-methyl-1, 3-dihydro-2H-indol-2-one
Variation a:
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-3-methyl-1, 3-dihydro-2H-indol-2-one (0.50g) and 1-methyl-1H-imidazole (0.37g) were added as starting materials to 5ml of dichloromethane and then cooled to-20 ℃. Difluoromethanesulfonyl chloride (0.58g) was added dropwise with stirring and the mixture was then slowly heated to room temperature. The mixture was stirred at room temperature for 3 hours. HPLC analysis detected starting material (67%), desired product (25%) and other components. The mixture is added to 10ml of water, the phases are separated and the organic phase is concentrated by evaporation in vacuo. The residue was purified by chromatography and the product was separated from unreacted starting material. The title compound is obtained in 86% HPLC purity (0.16g, 22% of theory). The structure as an N-sulfonylated compound can be confirmed by 2D-NMR.
LC-MS：M+H＝419(85％)。
1H-NMR(400MHz，CDCl3)：δ(ppm)＝7.10-7.25(m，3H)，6.67(t，1H)，4.02(s，6H)，1.94(s，3H)。
Variation B:
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-3-methyl-1, 3-dihydro-2H-indol-2-one (5.0g) was suspended in 40ml of dichloromethane. 1-methyl-1H-imidazole (6.47g) and 1, 4-dimethylpiperazine (1.78g) were added and the solution was stirred at 45 ℃ under nitrogen for 30 minutes. The reaction mixture was cooled to 0 ℃ and then a solution of difluoromethanesulfonyl chloride (11.9g) in 20ml of dichloromethane was added dropwise over 30 minutes, during which the temperature was maintained at 0 ℃. The mixture was post-stirred for one hour at 0 ℃. After addition of 200ml of dichloromethane, the organic phase is washed with 200ml of hydrochloric acid (2%) and water. To the organic phase, 100ml of acetonitrile and a few drops of N, N-dimethylformamide were added, followed by washing with 200ml portions of aqueous potassium hydroxide solution (3%) and water alternately for a plurality of times. Most of the solvent was distilled off under vacuum. The residue was dissolved in 50ml of toluene and washed three times with water. The solvent was distilled off under vacuum. The title compound is obtained in 93% HPLC purity (4.06g, 58% of theory).
The NMR signals of the products correspond to those of the products obtained according to variant A.
Example 13(═ comparative example 13):
preparation of 4-methylbenzenesulfonic acid 3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1H-indol-2-yl ester
Figure BDA0000369980320000381
3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -7-fluoro-1, 3-dihydro-2H-indol-2-one (1.15g), 4-methylbenzenesulfonyl chloride (1.06g) and sodium carbonate (0.41g) were added as starting materials to 5.5ml of water and 11ml of acetone, and then heated to 80 ℃ in a preheated oil bath with stirring. After 45 minutes, the hot solution was filtered, and the solid was washed with 20ml of water/acetone (1: 1) and methanol and dried under vacuum. 0.76g of product of 97% HPLC purity (42% of theory) are obtained. The structural elucidation by NMR confirmed it to be an O-sulfonylated product. Another 0.41g of product of 89% HPLC purity can be isolated by filtration (21% of theory).
LC-MS：M-H＝443(95％)。
1H-NMR(400MHz，DMSO-D6)：δ(ppm)＝13.33(s，1H)，8.12(d，1H)，7.64(d，2H)，7.30(d，2H)，7.10-7.22(m，2H)，3.97(s，6H)，2.33(s，3H)。
Example 14:
7-chloro-1- [ (difluoromethyl) sulfonyl ] -3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -1, 3-dihydro-2H-indol-2-one
Figure BDA0000369980320000382
7-chloro-3- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -1, 3-dihydro-2H-indol-2-one (6.0g) was added as a starting material to 150ml of dichloromethane. 1-methyl-1H-imidazole (6.3g) and 1, 4-dimethylpiperazine (4.4g) were added and the reaction mixture was stirred at room temperature for one hour. The mixture was cooled to-60 ℃ under nitrogen and then difluoromethanesulfonyl chloride (14.4g) was added dropwise slowly with stirring, during which the temperature was maintained below-50 ℃. The mixture was heated to-15 ℃ and held at this temperature for two days with occasional stirring. For the work-up, 50ml of water are added and most of the organic solvent is then distilled off under vacuum. The residue was filtered, washed with water, dissolved in 100ml of 2-propanol and stirred for one hour, filtered, washed with 2-propanol and methanol and dried. The title compound was obtained as a solid in 99% HPLC purity (5.2g, 65% of theory). The N-sulfonylation of the product was confirmed by UV absorption (maximum at 360nm) and 2D-NMR spectroscopy.
LC-MS：M+H＝421(100％)。
1H-NMR(400MHz，CDCl3)：δ(ppm)＝12.53(s，1H)，7.95(dd，1H)，7.13-7.21(m，2H)，6.96(t，1H)，4.21(s，3H)，4.16(s，3H)。

Claims (18)

1. A process for preparing N-sulfonyl substituted oxindoles of formula (3) having a 6-ring heteroaryl substituent (Q) in position 3,
Figure FDA0000369980310000011
wherein
R1aTo R1dIndependently of one another, are selected from
Hydrogen, fluorine, chlorine, bromine, iodine and a compound selected from
(C1-C6) -an alkyl group, wherein the alkyl group is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluorine, chlorine, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C3-C7) -cycloalkyl, wherein cycloalkyl is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)3-C7) -cycloalkyl or (C)1-C4) -a substituent of an alkoxy group,
(C1-C6) -alkoxy, wherein alkoxy is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C3-C7) -cycloalkoxy, wherein cycloalkoxy is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
(C1-C6) Alkylthio, wherein alkylthio is branched or unbranched and is unsubstituted or substituted by one or more substituents selected from the group consisting of fluorine, chlorine, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
(C3-C7) Cycloalkylthio, wherein cycloalkylthio is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)1-C4) -substituent of alkoxy, and
phenyl or 1-naphthyl or 2-naphthyl or a five-or six-membered heteroaromatic ring having 1 to 2 heteroatoms, wherein the heteroatoms are independently of one another selected from O or N and wherein aryl or heteroaryl is unsubstituted or substituted by one or more groups selected from fluorine, chlorine, bromine, iodine, (C)1-C4) Alkyl radicals, (C)1-C4) -alkoxy or (C)3-C7) -cycloalkyl or (C)1-C4) -substitutents of alkylthio, and
R2is composed of
(C1-C6) -alkyl, wherein alkyl is unsubstituted or fully or partially substituted by fluorine, or
(C3-C7) Cycloalkyl, wherein cycloalkyl is unsubstituted or fully or partially substituted by fluorine,
R3is composed of
Hydrogen or
(C1-C6) -an alkyl group, wherein the alkyl group is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluorine, chlorine, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C1-C6) Alkylthio, wherein alkylthio is unsubstituted or substituted by one or more groups selected from fluorine, chlorine, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
and is
Q is
A six-membered heteroaromatic ring having 1 to 3 nitrogen atoms, wherein the heteroaromatic ring is unsubstituted or substituted by one or more substituents selected from (C)1-C4) -alkyl or (C)1-C4) -alkoxy or (C)3-C7) -cycloalkyl or (C)3-C7) A cycloalkoxy group or (C)1-C4) -a substituent of an alkylthio group,
by oxindole compounds of the formula (1)
Figure FDA0000369980310000021
Wherein
R1aTo R1dAnd R3And Q has the meaning defined in formula (3),
reaction with sulfonyl compound (2) in a solvent
Figure FDA0000369980310000022
Wherein
R2Has the meaning defined in formula (3), and
x, as leaving group, is
Fluorine, chlorine, bromine, 1-imidazolyl, 1H-benzotriazolyloxy, 1H-benzotriazolyl or O-SO2-R7Wherein R is7Having the formula R2In the meaning defined in (1) and R2And R7Are the same or different, or
N(R8)SO2R9Wherein R is8Is carbonyl and R9Is unsubstituted or substituted phenyl, and R8And R9Either bonded to each other or not bonded to each other,
wherein the reaction is carried out in
An imidazole base substituted in position 1, or
-in the presence of a base mixture comprising at least one imidazole base substituted in position 1.
2. A process for preparing an N-sulfonyl-substituted 3-triazinyloxyindole of the formula (3-1) according to claim 1
Figure FDA0000369980310000031
Wherein
R1aTo R1dAnd R3Has the meaning as defined in claim 1, and
R2is (C)1-C6) -alkyl, or (C)3-C7) -cycloalkyl, wherein alkyl or cycloalkyl is fully or partially substituted by fluorine, and
R4and R5Independently of one another each is
The presence of hydrogen in the presence of hydrogen,
(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C1-C6) -alkoxy radicals, in whichAlkoxy is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluorine, chlorine, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
wherein the compound of formula (3-1), excluding,
-R1ais fluorine and
-R2is 2, 2-difluoroethyl or 1, 1, 1-trifluoroethyl.
3. The method of claim 1 or 2, wherein R3Is hydrogen.
4. The method of any one of claims 1 to 3, wherein R2Is difluoromethane.
5. The process according to any one of claims 1 to 4, wherein the imidazole base substituted in position 1 is-1- (C)1-C6) -an alkyl-1H-imidazole,
-1-(C1-C7) -cycloalkyl-1H-imidazole,
-1-benzyl-1H-imidazole,
-1-aryl-1H-imidazoles,
-1-heteroaryl-1H-imidazole, or
-mixtures comprising at least two specifically named imidazole bases substituted in position 1.
6. The process according to claim 5, wherein the imidazole base substituted in position 1, used alone or in mixtures, is 1-methyl-1H-imidazole, 1-butyl-1H-imidazole or 1-benzyl-1H-imidazole.
7. The process according to any one of claims 1 to 6, wherein the base mixture comprises at least one imidazole base substituted in the 1-position and further comprises at least one
-a tertiary amine base of formula (4) or
Figure FDA0000369980310000041
A substituted pyridine base of the formula (5) or
Figure FDA0000369980310000042
-a mixture of a tertiary amine base of formula (4) and a substituted pyridine base of formula (5).
8. The process of claim 7 wherein the tertiary amine base is selected from
Diazabicyclo [2.2.2] octane (DABCO),
-1-methylmorpholine,
-1-ethylmorpholine,
-N, N-dimethylpiperazine and
-1, 2-bis (dimethylamino) ethane.
9. The process as claimed in claim 7, wherein the pyridine base used is 5-ethyl-2-methylpyridine or 3-methylpyridine.
10. The process of any one of claims 1 to 9, wherein the reaction is carried out in the following solvent
-methylene chloride,
-2-methyltetrahydrofuran, or
-ethyl acetate, or
Mixtures of the specified solvents.
11. The process of any one of claims 1 to 10, wherein the addition of the reactants is carried out in one or more than two portions over a period of 0.05 to 6 hours.
12. The process of any one of claims 1 to 11, wherein the reaction temperature for sulfonylation is in the range of-20 ℃ to +10 ℃.
13. N-sulfonyl substituted 3-triazinyloxyindoles of formula (3-1)
Figure FDA0000369980310000051
Or a salt thereof (3-1a)
Figure FDA0000369980310000052
Wherein, in each case,
R1ato R1dIndependently of one another, are selected from
Hydrogen, fluorine, chlorine, bromine, iodine, and is selected from
(C1-C6) -an alkyl group, wherein the alkyl group is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluorine, chlorine, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C3-C7) -cycloalkyl, wherein cycloalkyl is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)3-C7) -cycloalkyl or (C)1-C4) -a substituent of an alkoxy group,
(C1-C6) -alkoxy, wherein alkoxy is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C3-C7) -cycloalkoxy, wherein cycloalkoxy is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
(C1-C6) Alkylthio, wherein alkylthio is branched or unbranched and is unsubstituted or substituted by one or more substituents selected from the group consisting of fluorine, chlorine, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
(C3-C7) Cycloalkylthio, wherein cycloalkylthio is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkyl or (C)1-C4) -substituent substitution of alkoxy, and
phenyl or 1-naphthyl or 2-naphthyl or a five-or six-membered heteroaromatic ring having 1 to 2 heteroatoms, wherein the heteroatoms are independently of one another selected from O or N, and wherein aryl or heteroaryl is unsubstituted or substituted by one or more groups selected from fluorine, chlorine, bromine, iodine, (C)1-C4) Alkyl radicals, (C)1-C4) -alkoxy or (C)3-C7) -cycloalkyl or (C)1-C4) -substituent substitution of alkylthio, and
R2is composed of
Methyl, wherein the methyl is completely or partially substituted by fluorine, or
(C3-C7) Cycloalkyl, wherein cycloalkyl is fully or partially substituted by fluorine,
R3is composed of
Hydrogen, or
(C1-C6) -an alkyl group, wherein the alkyl group is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluorine, chlorine, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C1-C6) Alkylthio, wherein alkylthio is unsubstituted or substituted by one or more groups selected from fluorine, chlorine, (C)1-C4) -alkyl or (C)1-C4) -a substituent of an alkoxy group,
R4and R5Independently of one another each is
The presence of hydrogen in the presence of hydrogen,
(C1-C6) -alkyl, wherein alkyl is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
(C1-C6) -alkoxy, wherein alkoxy is branched or unbranched and is unsubstituted or substituted by one or more groups selected from fluoro, chloro, (C)1-C4) -alkoxy or (C)3-C7) -a substituent of a cycloalkyl group,
wherein, in the salt of formula (3-1a), M is Li, Na, K, Cs, Ba, Mg, Ca, Zn, or N (R)c)4Wherein R iscH or (C)1-C6) -alkyl, and wherein the counterion M+Is determined by the specific charge to form an overall neutral compound of formula (3-1 a).
14. An N-sulfonyl substituted 3-triazinyl oxindole of formula (3-1) or a salt of formula (3-1a) according to claim 13, wherein
R1aTo R1dIndependently of one another, are selected from
Hydrogen, fluorine, chlorine, and
(C1-C6) -an alkyl group, wherein the alkyl group is branched or unbranched,
(C1-C6) -an alkoxy group, wherein the alkoxy group is branched or unbranched, and
R2is a difluoromethyl group or a trifluoromethyl group,
R3is a hydrogen atom, and is,
R4and R5Independently of one another each is
(C1-C4) -an alkyl group, wherein the alkyl group is branched or unbranched,
(C1-C4) -alkoxy, wherein the alkoxy is branched or unbranched,
wherein, in the salt of formula (3-1a), M is Na and K.
15. An N-sulfonyl substituted 3-triazinyl oxindole of formula (3-1) or a salt of formula (3-1a) according to claim 14, wherein
R1aTo R1dIndependently of one another, from hydrogen, fluorine, chlorine, methoxy, and
R2is a difluoromethyl group,
R3is hydrogen, and
R4and R5Independently of one another, are each methoxy.
16. An N-sulfonyl substituted 3-triazinyl oxindole of formula (3-1) or a salt of formula (3-1a) according to claim 15, wherein R1aTo R1dIndependently of one another, from hydrogen and fluorine.
17. An imidazole base substituted in position 1, or
-a base mixture comprising at least one imidazole base substituted in position 1,
use for the preparation of an N-sulfonyl substituted oxindole of formula (3) according to claim 1 or any one of claims 1 to 12 or of an N-sulfonyl substituted 3-triazinyl oxindole of formula (3-1) according to any one of claims 13 to 16, and salts thereof of formula (3-1 a).
18. Use of compounds of formula (3) prepared according to any one of claims 1 to 12 and compounds of formula (3-1) prepared according to any one of claims 13 to 16 and salts thereof (3-1a) as intermediates for the preparation of fine chemicals and active ingredients for agricultural use.
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MX2013007014A (en) 2013-07-29
US8969553B2 (en) 2015-03-03
IL227061A (en) 2017-12-31
JP2014505043A (en) 2014-02-27
US20140024828A1 (en) 2014-01-23
US20140005388A1 (en) 2014-01-02
US9096551B2 (en) 2015-08-04
ES2583061T3 (en) 2016-09-16

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